Epilepsy research has seen an explosion in new findings in recent years, with several new ion channel and receptor mechanisms gaining increasing prominence as potential underlying determinants of this disease. Despite this increase in potential novel therapeutic targets, there has been a relative dearth in actual clinical applications emerging from this body of work. Two major factors that may contribute to this translational gap are a) that the majority of studies are conducted at a cellular or subcellular level, and extrapolate consequences to circuit and whole animal excitability~ and b) that many studies assume that changes will occur globally, rather than in proscribed subsets of cells. Seizures, the underlying substrate of epilepsy, are a network property, and emerge from the integrated firing of diverse populations of neurons. To address this translational gap, we have developed research plan driven by our CENTRAL HYPOTHESIS: Only by studying the emergent properties of neurons within networks can we determine how cellular and subcellular changes may magnify (or conversely, be muted) by integration into circuit activation properties. To test this hypothesis, we will examine hippocampal excitability in animals with temporal lobe epilepsy, using a synergistic combination of state of the art functional imaging, patch clamp recording, and cellular manipulation and ablation techniques. This plan is centered on 3 Specific Aims: 1: Identify circuit disruptions in the entorhinal cortex/CA1 synaptic loop of animals with epilepsy~ 2: In identified entorhinal cortical and CA1 neurons which are behaving aberrantly during entorhinal cortical/CA1 loop circuit activation in animals with epilepsy, conduct cellular patch clamp, functional imaging, and anatomic studies to determine the cellular mechanisms mediating this aberrant function~ 3: Selectively activate or inhibit hippocampal and entorhinal cortical neurons during circuit activation in epileptic animals, and determine consequences on the propensity of the network to generate aberrant responses. In these studies, we will utilize a novel, comprehensive set of strategies: we will parse neurons into groups based on their network behavior, determine cellular mechanisms mediating the individual contribution of neurons to dynamic, pathological function of networks, and then conduct interventional studies testing the role of these 'hub'cells in generation of pathological activity. This should provide detailed understanding of the interplay between cellular abnormalities and network excitability, providing novel therapeutic targets for epilepsy control with demonstrable impact on circuit dynamics.

Public Health Relevance

(Relevance): Temporal lobe epilepsy is the most common form of epilepsy in adults, and among the least responsive to current drug treatment. One possible reason for difficulties in treating this disease is that we do not understand how neurons work in their natural environment in either normal or epileptic brain, and so cannot extrapolate what is seen in individual cells to mechanisms of seizure generation, which involves network activity. This project will examine mechanisms underlying epilepsy, using state of the art brain imaging techniques, recording neuronal activity in their natural environment during seizures. This will broaden our understanding of how seizures are generated, and may help to develop new therapies to better treat temporal lobe epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032403-20
Application #
8308548
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Whittemore, Vicky R
Project Start
1994-07-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
20
Fiscal Year
2012
Total Cost
$459,198
Indirect Cost
$180,050
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Yu, Esther P; Dengler, Christopher G; Frausto, Shanti F et al. (2013) Protracted postnatal development of sparse, specific dentate granule cell activation in the mouse hippocampus. J Neurosci 33:2947-60
Coulter, Douglas A; Yue, Cuiyong; Ang, Chyze Whee et al. (2011) Hippocampal microcircuit dynamics probed using optical imaging approaches. J Physiol 589:1893-903
Burton, Denise Y; Song, Cunxian; Fishbein, Ilia et al. (2003) The incorporation of an ion channel gene mutation associated with the long QT syndrome (Q9E-hMiRP1) in a plasmid vector for site-specific arrhythmia gene therapy: in vitro and in vivo feasibility studies. Hum Gene Ther 14:907-22
Coulter, Douglas A; McIntyre, Dan C; Loscher, Wolfgang (2002) Animal models of limbic epilepsies: what can they tell us? Brain Pathol 12:240-56
Crino, Peter B; Jin, Hong; Shumate, Melissa D et al. (2002) Increased expression of the neuronal glutamate transporter (EAAT3/EAAC1) in hippocampal and neocortical epilepsy. Epilepsia 43:211-8
Sepkuty, Jehuda P; Cohen, Akiva S; Eccles, Christine et al. (2002) A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy. J Neurosci 22:6372-9
Lin, D D; Cohen, A S; Coulter, D A (2001) Zinc-induced augmentation of excitatory synaptic currents and glutamate receptor responses in hippocampal CA3 neurons. J Neurophysiol 85:1185-96
Brooks-Kayal, A R; Shumate, M D; Jin, H et al. (2001) gamma-Aminobutyric acid(A) receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development. J Neurochem 77:1266-78
Cohen, A S; Lin, D D; Coulter, D A (2000) Protracted postnatal development of inhibitory synaptic transmission in rat hippocampal area CA1 neurons. J Neurophysiol 84:2465-76
Brooks-Kayal, A R; Shumate, M D; Jin, H et al. (1999) Human neuronal gamma-aminobutyric acid(A) receptors: coordinated subunit mRNA expression and functional correlates in individual dentate granule cells. J Neurosci 19:8312-8

Showing the most recent 10 out of 23 publications